FIELD OF THE INVENTION
The present invention in general relates to a pharmaceutical composition comprising a combination of a PDE-5 inhibitor and a 5a-reductase inhibitor or their pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof and at least one pharmaceutically acceptable excipient. The invention also provides a process for preparing such compositions.

BACKGROUND OF THE INVENTION
Benign prostatic hyperplasia (BPH) is an age-related phenomenon which has been found to occur in elderly men. BPH is associated with prostatic enlargement and bladder outlet obstruction that can cause significant lower urinary tract symptoms (LUTS). These LUTS have a negative impact on an individual’s quality of life, which is why treatment of symptomatic BPH has become a major priority. Although surgical interventions exist for treating BPH, pharmacological therapies are often preferred due to their minimal invasiveness and high degree of effectiveness. At present, there are three major classes of drugs approved for treating BPH, which include a) a-blockers, b) 5-a-reductase inhibitors (5-ARIs) and c) phosphodiesterase 5 (PDE-5) inhibitors, which are known to improve symptom relief through a variety of different mechanisms during monotherapy. Also, fixed dose combinations are expected to have synergistic effect in the treatment of BPH. The combination of 5-a-reductase inhibitors and phosphodiesterase 5 (PDE-5) inhibitors is of interest.

Tadalafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)–specific phosphodiesterase type 5 (PDE5). Chemically, tadalafil is known as pyrazino[1´,2´:1,6]pyrido [3,4–b]indole-1,4-dione, 6- (1,3-benzodioxol-5-yl)­2, 3, 6, 7, 12, 12a- hexahydro-2-methyl-, (6R,12aR)-. The structural formula is:

In the United States, tadalafil is available as Adcirca® and Cialis® tablets for oral administration from Eli Lilly. Adcirca® is available in 20 mg strength and is indicated for the treatment of pulmonary arterial hypertension (PAH). Cialis® is available in 2.5 mg, 5 mg, 10 mg and 20 mg strengths and is indicated for the treatment of erectile dysfunction (ED). Cialis is also indicated for the signs and symptoms of benign prostatic hyperplasia (BPH).

Finasteride is a synthetic 4-azasteroid compound and is a specific inhibitor of steroid Type II 5a-reductase, an intracellular enzyme that converts the androgen testosterone into 5a-dihydrotestosterone (DHT). Chemically, finasteride is known as 4-azaandrost-1-ene-17-carboxamide, N-(1,1-dimethylethyl)-3-oxo-(5a,17ß)-. The structural formula is:

In the United States, finasteride is available as Proscar® tablet for oral administration from Merck. Proscar® is available in 5 mg strength and is indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to improve symptoms, reduce the risk of acute urinary retention and reduce the risk of the need for surgery including transurethral resection of the prostate (TURP) and prostatectomy in monotherapy. It is also administered with alpha-blocker doxazosin to reduce the risk of symptomatic progression of BPH.

Approved label of Cialis® also recommends the use of tadalafil in combination with finasteride for treating BPH. The recommended dose of Cialis® for once daily use is 5 mg and finasteride is 5 mg, taken at approximately the same time every day for up to 26 weeks. However, both the drugs are administered separately or sequentially but no fixed dose combination dosage form is approved till date.

US 4760071 patent assigned to Merck and Co. discloses finasteride specifically.

US 5859006 patent assigned to Icos Corp. discloses tadalafil generically.

US 20080261995A1 patent application assigned to Pfizer Inc. discloses a pharmaceutical formulation comprising a combination of a PDE-5 inhibitor and a 5-alpha reductase inhibitor in the treatment of lower urinary tract symptoms (LUTS). The said patent application discloses a formulation comprising the combination of sildenafil and finasteride.

WO 2016003181A1 PCT application assigned to Hanmi Pharmaceutical discloses a core coat system with a specific film coating composition, wherein 5-a-reductase inhibitor is in coating.

Formulation design of combination of more than one active pharmaceutical ingredient (API) in a single dosage form is challenging as physical and chemical incompatibilities between the APIs and excipients may occur. Both tadalafil and finasteride are known to have physical and chemical incompatibility in the prior arts. Since both the drugs belong to BCS class II, development of the combination in single dosage form appears to be challenging. Moreover, several prior arts attempted to develop a formulation comprising tadalafil and 5a-reductase inhibitors combination, which are cost sensitive, difficult to manufacture and time consuming. Hence, there is a need to develop an improved formulation, which is cost effective and easy to industrialize.

Inventors of the present invention propose dosage forms comprising the combination of 5-a-reductase inhibitors and PDE-5 inhibitors, specifically tadalafil and finasteride. The proposed dosage forms are bilayer tablets, inlay tablets, capsules, powder for oral suspension comprising either two different types of pellets, granules, mini-tablets, one drug in tablet surrounded by second drug in powder form.
The inventors of the present invention propose a pharmaceutical composition, which is expected to exhibit desired pharmaceutical technical attribute.

SUMMARY OF THE INVENTION
It is an object of the present invention to develop a pharmaceutical composition comprising a combination of PDE 5 inhibitor and a 5a-reductase inhibitor.

Another object of the present invention is to develop a pharmaceutical composition comprising a combination of tadalafil and finasteride and their pharmaceutically acceptable salts and solvates thereof, wherein the composition is in the form of pellets, granules, beads, spheroids, mini-tablets to be encapsulated in a capsule, powder for oral suspension dispensed as sachets, tablet in tablet, inlay tablet, bilayer tablet or multilayer tablet.

Yet another object of the invention is to formulate a pharmaceutical composition of the said combination which is expected to exhibit desirable technical attributes like stability, dissolution and assay.

DESCRIPTION OF THE INVENTION
The present invention can be more readily understood by reading the following detailed description of the invention and study of the included examples.
As used herein, the term “composition”, as in pharmaceutical composition, is intended to encompass a drug product comprising an active or its pharmaceutically acceptable salt or derivative thereof, and the other inert ingredient(s) (pharmaceutically acceptable excipients). Such pharmaceutical compositions are synonymous with “formulation” and “dosage form”. Pharmaceutical composition of the invention includes, but is not limited to, powder for oral suspension, pellets, beads, minitabs, spherules, beadlets, microcapsules, millispheres, microspheres, powder, granules, spheroids and the like filled in sachet, tablets, orally disintegrating tablets, capsules, ready to use suspension, chewable tablets, bilayer tablets, in-lay tablets, tablet in tablet, monolithic tablet, multilayer tablet and the like. Preferably, the pharmaceutical composition refers to powder, granules, pellets, mini-tablets filled into capsules. More preferably, the pharmaceutical composition refers to powder, granules, pellets with different API’s compressed into monolithic, bilayer, inlay and multilayer tablet.

The term “core” as used herein refers to pellets/spheres/granules/uncoated tablets comprising at least one or more other excipients selected from diluent, sweetener, binder, disintegrant, lubricant, glidant and the like and optionally one or more API.

The term “multiparticulate” used herein refers to a plurality of discrete or aggregated particles, pellets, beads, spheroids, spheres or mixture thereof, irrespective of their size, shape or morphology.

The term "excipient" means a pharmacologically inactive component such as a diluent, binder, disintegrant, lubricant, surfactant, carrier or the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for veterinary as well as human pharmaceutical use. Reference to an excipient includes both one and more than one such excipient. Co-processed excipients are also covered under the scope of present invention. Further, excipient may be in the form of powders or in the form of dispersion. Combination of excipients performing the same function may also be used to achieve desired formulation characteristics.

As used herein, the term "about" means ± approximately 10% of the indicated value.
The term “w/w” as used herein refers the total weight of the core composition.

The term “sachet” as used herein refers to any suitable container, package or bag to contain the dry powder composition. The sachet may be formed of any suitable material, including plastic, metal foil, paper or a combination thereof. Sachet can be three layered with sandwiched polyethylene terephthalate (PET) /aluminium/polyethylene layers or four layered or more with addition of more layers of PET/aluminium/polyethylene to provide robust protection to moisture sensitive drugs. The sachet may be provided with any suitable means for opening thereof, including a perforated region or a nick in the edge of the sachet for ease of tearing. The sachet may be of any suitable size. The sachet is sealed using any appropriate method. Particularly, the sachet is disposable. Sachet can be a child resistant container.

In one embodiment, the present invention relates to a pharmaceutical composition comprising a combination of a PDE-5 inhibitor and a 5a-reductase inhibitor.

Another embodiment of the present invention relates to a pharmaceutical composition comprising a combination of PDE-5 inhibitor and a 5a-reductase inhibitor, wherein the 5a-reductase inhibitors is selected from finasteride, dutasteride, epristeride or alfatradiol and PDE-5 inhibitor is selected from tadalafil, sildenafil, vardenafil, avanafil, lodenafil, mirodenafil, udenafil, zaprinast, icariin, benzamidenafil, dasantafil or gisadenafil.

Another embodiment of the present invention relates to a pharmaceutical composition comprising a combination of tadalafil and finasteride and their pharmaceutically acceptable salts and solvates thereof.

Yet another embodiment of the present invention relates to a pharmaceutical composition comprising a combination of tadalafil and finasteride and their pharmaceutically acceptable salts and solvates thereof, wherein the composition is in the form of pellets or granules or beads or spheroids or mini-tablets, multiparticulates or powder or combinations thereof; to be encapsulated in the capsule or dispensed as sachets; tablet in tablet; inlay tablet; bilayer tablet or multilayer tablet.

In an embodiment, the present invention relates to a pharmaceutical composition comprising a combination of tadalafil and finasteride and their pharmaceutically acceptable salts and solvates thereof, wherein the composition comprises of:
a) about 1.0 to 90.0% by weight of tadalafil, or a pharmaceutically acceptable salt thereof,
b) about 1.0 to 80.0% by weight of finasteride, or a pharmaceutically acceptable salt thereof,
c) at least one pharmaceutically acceptable excipient,
wherein the composition is free of disintegrant.

In another embodiment of the present invention, the pharmaceutical composition comprises of a combination of tadalafil and finasteride and their pharmaceutically acceptable salts and solvates thereof, wherein the composition comprises of:
a) about 1.0 to 90.0% by weight of tadalafil, or a pharmaceutically acceptable salt thereof,
b) about 1.0 to 80.0% by weight of finasteride, or a pharmaceutically acceptable salt thereof,
c) at least one pharmaceutically acceptable excipient,
wherein the composition is free of binder.

In yet another embodiment of the present invention, the pharmaceutical composition comprises of a combination of tadalafil and finasteride and their pharmaceutically acceptable salts and solvates thereof, wherein the composition comprises of:
a) about 1.0 to 90.0% by weight of tadalafil, or a pharmaceutically acceptable salt thereof,
b) about 1.0 to 80.0% by weight of finasteride, or a pharmaceutically acceptable salt thereof,
c) at least one pharmaceutically acceptable excipient,
wherein the composition is free of surfactant.

In another embodiment of the present invention, the pharmaceutical composition comprises of a combination of tadalafil and finasteride and their pharmaceutically acceptable salts and solvates thereof, wherein the composition comprises of two populations of granules:
a) first population of granules comprising of tadalafil and atleast one pharmaceutical excipient, and
b) second population of granules comprising of a finasteride and a pharmaceutical excipient,
c) at least one pharmaceutically acceptable excipient,
wherein the composition is free of disintegrant.

In another embodiment of the present invention, the pharmaceutical composition comprises of a combination of tadalafil and finasteride and their pharmaceutically acceptable salts and solvates thereof, wherein the composition comprises of two populations of granules:
a) first population of granules comprising of tadalafil and atleast one pharmaceutical excipient, and
b) second population of granules comprising of a finasteride and a pharmaceutical excipient,
c) at least one pharmaceutically acceptable excipient,
wherein the composition is free of binder.

In another embodiment of the present invention, the pharmaceutical composition comprises of a combination of tadalafil and finasteride and their pharmaceutically acceptable salts and solvates thereof, wherein the composition comprises of two populations of granules:
a) first population of granules comprises of tadalafil and atleast one pharmaceutical excipient, and
b) second population of granules comprises of finasteride and a pharmaceutical excipient,
c) at least one pharmaceutically acceptable excipient,
wherein the composition is free of surfactant.

In another embodiment of the present invention, the pharmaceutical excipients are selected from the group comprising binders, diluents, surfactants, lubricants, glidants, disintegrants, alkaline substances, tonicity adjusting agents, wetting agents, buffering substances, solubilizers, complexing agents, taste masking agents, colorants, plasticizers, preservatives and any combination thereof.

In another embodiment of the present invention, the pharmaceutical composition comprises of a combination of tadalafil and finasteride and their pharmaceutically acceptable salts and solvates thereof wherein the composition comprises of:
a) an inert core,
b) first coating layer comprising tadalafil in an amount from about 1.0-90.0%w/w and at least a pharmaceutical excipient over the core, and
c) second coating layer comprising finasteride in an amount from about 1.0-90.0%w/w and atleast one pharmaceutical excipient,
wherein first and second coating layers are separated optionally by a seal coat.

Yet another embodiment of the present invention relates to a pharmaceutical composition comprising a combination of tadalafil and finasteride and their pharmaceutically acceptable salts and solvates thereof wherein the composition comprises of two populations of granules:
a) first population of granules comprising of tadalafil and atleast one pharmaceutical excipient, and
b) second population of granules comprising of finasteride and a pharmaceutical excipient,
wherein both the granules are blended and compressed into tablets or bilayer tablets or filled into capsules or sachet.

Another embodiment of the present invention relates to a process of preparation of a pharmaceutical composition comprising a combination of tadalafil and finasteride and their pharmaceutically acceptable salts and solvates thereof, wherein the process comprises:
a) preparing a first population of granules comprising tadalafil and atleast one pharmaceutical excipient, and
b) preparing a second population of granules comprising finasteride and a pharmaceutical excipient,
c) lubricating the first population of granules and compressed into mini-tablet,
d) encapsulating the mini-tablet of first population and granules of second population in a capsule.

In yet another embodiment of the present invention relates to a process of preparation of a pharmaceutical composition comprising a combination of tadalafil and finasteride and their pharmaceutically acceptable salts and solvates thereof wherein the process comprises:
a) preparing a first population of granules comprising tadalafil and a pharmaceutical excipient, and
b) preparing a second population of granules comprising finasteride and a pharmaceutical excipient,
c) lubricating the second population of granules and compressed into mini-tablet,
d) encapsulating compressed mini-tablet of second population and granules of first population in a capsule.

In another embodiment of the present invention, the capsule shell can be gelatin based or HPMC (hydroxypropyl methylcellulose or hypromellose) based or PVA (Polyvinl acetate) based or cellulose ether film based or starch based.

In another embodiment of the present invention, the pharmaceutical composition comprises of a combination of tadalafil and finasteride and their pharmaceutically acceptable salts and solvates thereof, wherein the composition comprises of:
a) a core comprising finasteride in an amount from about 1.0-90.0%w/w and at least a pharmaceutical excipient, and
b) coating layer comprising tadalafil in an amount from about 1.0-90.0%w/w and a pharmaceutical excipient.

Another embodiment relates to a pharmaceutical composition comprising a combination of tadalafil and finasteride and their pharmaceutically acceptable salts and solvates thereof wherein the composition is a bilayer tablet comprising:
a) first layer comprises of tadalafil in an amount from about 1.0-90.0%w/w, cyclodextin and at least one pharmaceutical excipient, and
b) second layer comprises of a finasteride and at least one pharmaceutical excipient,
wherein both the layers are compressed into a tablet.

Another embodiment of the present invention relates to a process for preparation of a pharmaceutical composition comprising a combination of tadalafil and finasteride and their pharmaceutically acceptable salts and solvates thereof wherein the process comprises of:
a) dry mixing tadalafil with pharmaceutical excipients like binder, disintegrant and diluent,
b) granulating the resultant blend as obtained in step a) with aqueous /non-aqueous binder solution,
c) passing the wet mass as obtained in step b) through suitable size sieve and drying the granulates in a suitable drying equipment,
d) passing the resultant granules through a suitable size mesh and mixing with lubricants and glidants,
e) repeating step a)-d) for finasteride granules,
f) compressing the lubricated granules of tadalafil and finasteride into tablet core or bilayer tablets.

Another embodiment of the present invention relates to a process for preparation of a pharmaceutical composition comprising a combination of tadalafil and finasteride and their pharmaceutically acceptable salts and solvates thereof, wherein the process comprises of:
a) dry mixing tadalafil with pharmaceutical excipients like binder, disintegrant and diluent,
b) slugging/roller compacting the resultant blend as obtained in step a)
c) passing the slugs/compacts as obtained in step b) through suitable size sieve,
d) passing the resultant granules through a suitable size mesh and mixing with lubricants and glidants,
e) repeating step a)-d) for finasteride granules,
f) compressing the lubricated granules into a tablet core or bilayer tablet.

Another embodiment of the present invention also provides a method for the preparation of the granules of pharmaceutical composition comprising the steps of:
a) dry mixing active ingredient with pharmaceutical excipients like binder, disintegrant and diluent,
b) granulating the resultant blend as obtained in (a) with aqueous binder/non-aqueous solution,
c) passing the wet mass as obtained in step (b) through suitable size sieve and drying the granulates in a suitable drying equipment,
d) passing the resultant granules of step (a) and (b) through a suitable size mesh and mixing the same with lubricants and glidants,
e) compressing the lubricated granules into tablet core or bilayer tablets.

In another embodiment of the present invention relates to the a pharmaceutical composition comprising a combination of tadalafil and finasteride and their pharmaceutically acceptable salts and solvates thereof, wherein the pharmaceutical excipient in the granules is selected from the group comprising suspending/thickening agent, a binder, a filler, a surfactant, an anti- tacking agent, a plasticizer, a lubricant, a glidant, a disintegrant, an alkaline substance, a diluent, a tonicity adjusting agent, a wetting agent, a buffering substance, a colorant, a preservative, and any combination thereof.

In another embodiment of the present invention relates to the pharmaceutical composition comprising a combination of tadalafil and finasteride and their pharmaceutically acceptable salts and solvates thereof, wherein the process of preparing the granules is selected from dry granulation, wet granulation, blending, extrusion spheronization, multiparticulate system (MUPS) and hot melt extrusion.

Another embodiment of the present invention relates to a pharmaceutical composition comprising a combination of tadalafil and finasteride and their pharmaceutically acceptable salts and solvates thereof wherein the dose of Tadalafil is about 2 mg to 40 mg and finasteride dose is from about 1 mg to 10 mg.

In further embodiment, the present invention includes method of using pharmaceutical composition comprising a combination of tadalafil and finasteride and their pharmaceutically acceptable salts thereof in the treatment of the patients with average severity of LUTS associated with BPH.

Another embodiment of the present invention relates to a pharmaceutical composition comprising a combination of tadalafil and finasteride and their pharmaceutically acceptable salts and solvates thereof wherein the drug is present in an amount of about 1.0 to about 90.0% w/w of the total composition; preferably from about 10.0 to about 70.0% w/w of the total composition; more preferably from about 5.0 to about 50.0% w/w of the total composition.

The pharmaceutical composition of the present invention can be packaged in a suitable pack/container such as amber colored polyethylene terephthalate (PET) bottle, glass bottle, high density polyethylene (HDPE) bottle, low density polyethylene (LDPE) bottle, Alu-Alu blisters, PA/Alu/PVC/Alu blisters, polypropylene (PP) bottle, packets, pouches, sachets and the like. The glass or plastic bottle is provided with a child proof closure. The package can include a syringe or a dispensing cup for ease of dosing.

In another embodiment of the present invention, there is provided a process for the preparation of a powder for suspension composition, granules or multiparticulates of drug or its pharmaceutically acceptable esters, salts, solvates, polymorphs, enantiomers or mixtures thereof by using conventional methods known in the art but not limited to blending, mixing, granulation, hot-melt extrusion, spray drying, spray coating techniques. Suitable solvents include aqueous or organic solvents. Preferable solvents include, but are not limited to, water, esters such as ethyl acetate; ketones such as acetone; alcohols such as methanol, ethanol, isopropanol, butanol; dichloromethane, chloroform, dimethyl acetamide (DMA), dimethyl sulfoxide (DMSO), ether, diethyl ether and combinations thereof. Preferably, the solvent used during wet mass preparation is water.
In another embodiment of the invention, wet granulation can be performed using rapid mixer granulator, fluid bed granulator, planetary mixer and the like; dry blending can be performed in V-blender or key blender; spheronization can be performed using Fuji paudal spheronizer or by any other method known in the art.
The wet granulation process according to the present invention may be any suitable wet granulation process preferably selected from the group consisting of fluidized bed granulation, mixing granulation, extruder granulation, disc granulation, and roller granulation, wherein fluidized bed granulation is particularly preferred.

Diluents or fillers or carriers are substances which usually provide bulk to the composition. Various useful fillers or diluents include, but are not limited to microcrystalline cellulose, calcium carbonate, calcium phosphate, dibasic anhydrous, calcium phosphate, dibasic dihydrate, calcium phosphate tribasic, calcium sulphate, cellulose powdered, cellulose acetate, compressible sugar, confectioner's sugar, dextrates, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, polydextrose, simethicone, sodium alginate, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, trehalose and xylitol, or mixtures thereof. The diluent is present in an amount of about 5.0 to about 98.0% w/w of the total composition.

Binders impart cohesiveness to formulation. Various useful binders include, but are not limited to hypromellose, acacia, alginic acid, carbomer, sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, glucose, guar gum, hydroxypropylcellulose, maltose, methylcellulose, povidone, copovidone, starch, polyvinyl alcohol or polyethylene oxide, or mixtures thereof. The binder may constitute from 0.0% to about 20.0% w/w of the pharmaceutical composition.

Glidants improve flowability and accuracy of dosing. Since the present invention relates to an oral pharmaceutical composition, it is imperative to use glidant(s) to achieve desirable flowability of the active. Glidants used in the composition include, but are not limited to, tribasic calcium phosphate, calcium silicate, cellulose, powdered, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, starch and talc or mixtures thereof. The amount of glidant ranges from about 0.1% to about 5.0% by weight of the composition.

Surfactants or surface-active agents improve wettability of the dosage form and/or enhance its dissolution. Surfactants contemplated in the present invention include but are not limited to anionic surfactants, amphoteric surfactants, non-ionic surfactants and macromolecular surfactants. Suitable examples of anionic surfactants include but are not limited to sodium lauryl sulphate, sodium cetyl stearyl sulphate or sodium dioctyl sulphosuccinate, docusate sodium etc. Suitable example of an amphoteric surfactant includes but is not limited to lecithin. Suitable examples of non-ionic surfactants include but is not limited to cetyl alcohol, stearyl alcohol, cetyl stearyl alcohol, cholesterol, sorbitan fatty acid esters such as sorbitan mono-oleate, polyoxyethylene sorbitan fatty acid esters such as polysorbate 80, polysorbate 20, polyoxyethylene fatty acid glycerides such as macrogol 1000 glycerol monostearate, polyoxyethylene fatty acid esters such as polyoxyl 40 stearate, polyoxyethylene fatty alcohol ethers such as polyoxyl 10 oleyl ether, glycerol fatty acid esters such as glycerol monostearate, commercially available SEPITRAP® 80 or SEPITRAP® 4000 etc. The surfactant may constitute from 0.0% to about 5.0% by weight of composition.

Disintegrants selected from the group consisting of crospovidone, modified starches, croscarmellose sodium, sodium starch glycolate, low substituted Hydroxypropyl cellulose and carboxymethylcellulose calcium. These disintegrants are also known as superdisintegrants. The disintegrant may constitute from 0.0% to 20.0% by weight of the pharmaceutical composition.

Various useful preservatives include, but are not limited to, parabens such as methylparaben, propylparaben, butyl paraben and their salts, sorbic acid, sodium sorbate, potassium sorbate, calcium sorbate, benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, methyl hydroxybenzoate, ethyl para-hydroxybenzoate, sodium ethyl para-hydroxybenzoate, sodium metabisulphite, chlorhexidine, diazolidinyl urea, sodium citrate, butylated hydroxyl toluene (BHT), butylated hydroxyl anisole (BHA), tocopherol, ethylenediamine tetraacetic acid, propyl gallate, quaternary compounds, e.g. benzalkonium chloride and cetylpyridinium chloride, phenyl ethyl alcohol and the like. In particular, the preservative is selected from benzoic acid and its salts and/or parabens. The preservative is present in an amount of about 0.001% w/w to about 3.0% w/w.

Various useful antioxidants include, but are not limited to, ascorbic acid, tert-butylhydroquinone, sodium pyrosulfite, glutathione, sodium bisulfite, sodium sulfite, a-tocopherol, a-tocopherol acetate, monothioglycerol, cysteine, ascorbyl palmitate, acetylcysteine, dithiothreitol, sodium metabisulfite, thiourea, sodium thiosulfate, butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT) and propyl gallate.

Various useful sweetening agents include, but are not limited to, sugar or a sugar alcohol such as sucrose, dextrose, sucralose, sorbitol, neotame, aspartame, Acesulfame K, fructose, mannitol and invert sugar and sugar substitutes such as saccharin sodium. Sugar or a sugar alcohol can also act as filler. Preferably sweetening agent used is sodium saccharin, sucralose, neotame. The amount of sweetening agent ranges from about 0.05% to about 85.0% by weight of the composition.

The effervescent couple are selected from citric acid or sodium hydrogen citrate and sodium bicarbonate but other physiologically acceptable and/alkaline or alkaline earth metal carbonate mixtures may be used, for example tartaric, adipic, fumaric or malic acid, and sodium, potassium or calcium bicarbonates or sodium glycine carbonate.

Various useful flavoring agents, include, but are not limited to, flavors such as banana, lemon, orange, grape, lime and grapefruit, vanilla, and fruit essence, including apple, banana, pear, peach, strawberry, raspberry, cherry, plum, wild cherry, walnut, chocolate, pineapple, apricot; synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plant leaves, flowers, fruits such as cinnamon oil, oil of wintergreen, peppermint oils, clove oil, citrus oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, oil of bitter almonds, mint and cassia oil; maltol, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid and combinations thereof. Preferably, wild cherry, walnut, chocolate, pineapple, apricot, anise, banana and orange. Flavoring agent is present in the concentration of 0.1 - 1.0 % w/w. Although flavoring agent in lesser concentrations than 0. l% w/w or in higher concentrations than l% w/w can be used. The concentration of flavoring agent is flavor specific and may be modulated depending upon the flavour/s used.

Suitable coloring agent are selected from the group comprising FD&C (Federal Food, Drug and Cosmetic Act) approved coloring agents, natural coloring agents, natural juice concentrates, pigments such as iron oxide, titanium dioxide, and zinc oxide, and combinations thereof.

Various useful pH adjusting agent or buffering agents include, but are not limited to, citrate buffers, phosphate buffers, or any other suitable buffer known in the art including monosodium dibasic phosphate, meglumine, gluconic acid, lactic acid, citric acid, acetic acid, sodium gluconate, sodium lactate, sodium citrate, sodium acetate potassium citrate, sodium bicarbonate, potassium bicarbonate, sodium dihydrogen phosphate and potassium dihydrogen phosphate.

In another embodiment, the pharmaceutical composition of the present invention comprises of a particle form comprising tadalafil or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof from about 0.1 mg to about 40.0 mg in the formulation, preferably 1.0-20.0 mg, more preferably 2.5-10.0 mg.

In another embodiment, the pharmaceutical composition of the present invention comprises of a particle form comprising finasteride or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof from about 0.1 mg to about 20.0 mg in the formulation, preferably 1.0-10.0 mg, more preferably 1.0-5.0 mg.

Various useful taste masking agents include, but are not limited to, water soluble and/or insoluble polymeric excipient, water insoluble non-polymeric excipient, adsorbent, carbomer, alkali metal chlorides, cyclodextrins, ion exchange resin or an alkaline earth metal chlorides or a derivative thereof.

Suitable alkaline agents include, but are not limited to, pharmacologically alkali metal, alkaline earth metal or metal salts of weak acids such as sodium carbonate which can be anhydrous or hydrous, calcium carbonate and magnesium carbonate and the pharmacologically hydroxides and oxides of alkaline earth and earth metals such as magnesium hydroxide and magnesium oxide. The alkaline agent may constitute from 0.0% to about 10.0% by weight of the pharmaceutical composition.

The final formulations may be coated or uncoated. For coating, additional excipients such as film-forming polymers, plasticizers, antiadherents and opacifiers are used.

Various water-soluble polymers used to form a barrier/seal or film over the core. Examples include but are not limited to cellulose derivatives such as soluble alkyl- or hydroalkylcellulose derivatives such as methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethylethyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, etc., acidic cellulose derivatives, dextrins, starches and starch derivatives, polymers based on carbohydrates and derivatives thereof, natural gums such as gum Arabic, xanthans, alginates, polyacrylic acid, polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, chitosan and derivatives thereof, shellac and derivatives thereof, waxes and fat substances. If desired, the films may contain additional adjuvants for coating such as plasticizers, polishing agents, colorants, pigments, antifoaming agents, opacifiers, antisticking agents, and the like.

In another embodiment of the invention, water insoluble polymers suitable for use in the present invention include, but are not limited to, cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), ethylcellulose (EC), polyvinyl acetate phthalate methylcellulose acetate phthalate (MCAP) and methacrylic acid copolymers or its derivatives. Kollicoat® from Evonik Industries, Colorcon, Eastman Chemical and BASF Fine Chemicals respectively. Acrylate polymers or Methacrylic acid copolymers or its derivatives are selected from the group comprising different grades of Poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) 1:2:1, Poly(methacrylic acid, methyl methacrylate) 1:2, Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2, Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1, Poly(methacrylic acid, ethyl acrylate) 1:1.

In another embodiment the present invention includes particle size of free drug particulate form of drug or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, wherein particle diameter at 90% cumulative volume (d90) is less than about 100 µm, preferably less than 50 µm. Particle diameter at X% cumulative Particle size reduction can be performed by techniques including but not limited to fluid energy milling, ball milling, colloid milling, roller milling, hammer milling and the like. Particle size and particle size distribution can be measured by techniques such as Laser light scattering (e.g. Malvern Light Scattering), Coulter counter, microscopy and the like.

In yet another embodiment of the present invention, the multiparticulate based composition is packed in a packaging material selected from the group comprising of a foil, a pouch, a sachet, capsule, bottle, container or other suitable package.

The pharmaceutical oral dosage form prepared by the above mentioned process can be subjected to in vitro dissolution evaluation according to Test 711 "Dissolution" in the United States Pharmacopoeia 37, United States Pharmacopoeial Convention, Inc., Rockville, Md., 2014 ("USP") to determine the rate at which the active substance is released from the dosage form, and the content of the active substance can be determined in solution by high performance liquid chromatography.
Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail method for the preparation and testing of the pharmaceutical composition. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. Following examples are set out to illustrate the invention and do not limit the scope of the present invention.

EXAMPLES
The following non-limiting examples are intended to further illustrate certain preferred embodiments of the invention. They are, however not intended to be limiting the scope of the present invention in any way.
Pharmaceutical composition may be prepared by using quantitative formula as given in the following examples:
Table 1: Tablet formulation
Composition
S. No. Ingredients %w/w
I II III
First population of granules
1. Tadalafil 1-85 1-20 1-40
2. Microcrystalline cellulose 0-80 -- --
3. Dibasic calcium phosphate, Anhydrous -- 0-35 --
4. Mannitol -- -- 10-30
5. Crospovidone 0.1-15 -- --
6. Croscarmellose sodium -- 0-15 --
7. sodium lauryl sulfate 0.5-10 -- --
8. Polysorbate 80 -- -- 0-10
9. Povidone 0-10 -- 0.5-10
10. Hypromellose -- 0.5-10 --
11. Purified water q.s q.s q.s.
Second population of granules
12. Finasteride 1-80 1-10 1-20
13. Microcrystalline cellulose 0-80 5-30 --
14. Mannitol -- -- 10-50
15. Docusate sodium 0.5-5 -- --
16. sodium lauryl sulfate -- -- 0-5
17. Crospovidone / sodium starch glycolate 0-20 0-20 0.5-20
18. Povidone 0.5-10 0-10 0.10
Lubrication
19. Magnesium stearate 1-10 1-10 1-10
20. Talc 0-10 0-10 0.5-10

First and second population of granules are prepared by wet granulation/dry granulation or hot melt extrusion and compressed to tablets, wherein the tablet may be a bilayer tablet, trilayer tablet, multilayer tablet, in-lay tablet or tablet in tablet.
Table 2: Capsule formulation
Composition
S. No. Ingredients %w/w
I II
First population of granules
1. Tadalafil 1-80 1-80
2. Mannitol 0-80 0-80
3. Crospovidone 0-20 --
4. Sodium lauryl sulfate 0-5 --
5. HPß-CD -- 0-30
6. Povidone 0-10 0-10
7. Purified water q.s q.s
Second population of granules
8. Finasteride 1-80 1-80
9. Microcrystalline cellulose 0-80 0-80
10. Polysorbate 80 -- 0-5.0
11. Croscarmellose sodium 1-20 1-20
Lubrication
12. Calcium stearate 1-10 1-10
13. Talc 0-10 0-10

First and second population of granules are prepared by wet granulation/dry granulation and blended together and encapsulated in HPMC based or gelatin based or PVA based capsule shells.

We Claim:
1. A pharmaceutical composition comprising a combination of tadalafil and finasteride and their pharmaceutically acceptable salts and solvates thereof wherein the composition comprises of:
a) about 1.0 to 90% by weight of tadalafil, or atleast one pharmaceutically acceptable salt thereof,
b) about 1.0 to 80% by weight of finasteride, or a pharmaceutically acceptable salt thereof,
c) at least one pharmaceutically acceptable excipient,
wherein the composition is free of disintegrant.

2. A pharmaceutical composition comprising a combination of tadalafil and finasteride and their pharmaceutically acceptable salts and solvates thereof wherein the composition comprises of:
a) about 1.0 to 90% by weight of tadalafil, or atleast one pharmaceutically acceptable salt thereof,
b) about 1.0 to 80% by weight of finasteride, or a pharmaceutically acceptable salt thereof,
c) at least one pharmaceutically acceptable excipient,
wherein the composition is free of binder.

3. A pharmaceutical composition comprising a combination of tadalafil and finasteride and their pharmaceutically acceptable salts and solvates thereof wherein the composition comprises of:
a) about 1.0 to 90% by weight of tadalafil, or atleast one pharmaceutically acceptable salt thereof,
b) about 1.0 to 80% by weight of finasteride, or a pharmaceutically acceptable salt thereof,
c) at least one pharmaceutically acceptable excipient,
wherein the composition is free of surfactant.

4. The pharmaceutical composition of claims 1-3, wherein the composition is in the form of bilayer tablets, multilayer tablets, tablet in tablet, in-lay tablets, monolithic tablets and capsules containing two types of granules or pellets or mini-tablets containing different drugs.

5. A pharmaceutical composition comprising a combination of tadalafil and finasteride and their pharmaceutically acceptable salts and solvates thereof wherein the composition comprises of two populations of granules:
a) first population of granules comprising tadalafil and atleast one pharmaceutical excipient, and
b) second population of granules comprising finasteride and a pharmaceutical excipient,
c) at least one pharmaceutically acceptable excipient,
wherein the composition is free of disintegrant.

6. A pharmaceutical composition comprising a combination of tadalafil and finasteride and their pharmaceutically acceptable salts and solvates thereof wherein the composition comprises of two populations of granules:
a) first population of granules comprising tadalafil and atleast one pharmaceutical excipient, and
b) second population of granules comprising finasteride and a pharmaceutical excipient,
c) at least one pharmaceutically acceptable excipient,
wherein the composition is free of binder.

7. A pharmaceutical composition comprising a combination of tadalafil and finasteride and their pharmaceutically acceptable salts and solvates thereof wherein the composition comprises of two populations of granules:
a) first population of granules comprising tadalafil and atleast one pharmaceutical excipient, and
b) second population of granules comprising finasteride and a pharmaceutical excipient,
c) at least one pharmaceutically acceptable excipient,
wherein the composition is free of surfactant.

8. The pharmaceutical composition of claims 1-7, wherein the pharmaceutical excipient is selected from the group comprising a binder, a diluent, a surfactant, a lubricant, a glidant, a disintegrant, an alkaline substance, a tonicity adjusting agent, a wetting agent, a buffering substance, suspending/thickening agent, a colorant, a plasticizer, a preservative, and any combination thereof.

9. A pharmaceutical composition comprising a combination of tadalafil and finasteride and their pharmaceutically acceptable salts and solvates thereof wherein the composition comprises of :
c) an inert core,
d) first coating layer comprising tadalafil in an amount from about 1.0-90.0%w/w and at least a pharmaceutical excipient,
e) second coating layer comprising finasteride in an amount from about 1.0-90.0%w/w and a pharmaceutical excipient,
wherein first and second coating layer are separated optionally by a seal coat.

10. A process for preparation of a pharmaceutical composition comprising a combination of tadalafil and finasteride and their pharmaceutically acceptable salts and solvates thereof wherein the process comprises of:
a) dry mixing tadalafil with pharmaceutical excipients like binder, disintegrant and diluent,
b) granulating the resultant blend as obtained in step a) with aqueous/non-aqueous binder solution,
c) passing the wet mass as obtained in step b) through suitable size sieve and drying the granulates in a suitable drying equipment,
d) passing the resultant granules through a suitable size mesh and mixing with lubricants and glidants,
e) repeating step a) to d) for finasteride granules,
f) compressing the lubricated granules into tablet core or bilayer tablets.